With the variations of dietary life in recent years, it becomes a subject of discussion that the increase of obesity, diabetes mellitus, hypertension, hyperlipemia, with the background of lack of balance in in vivo energy, is a factor leading to occurrence of arteriosclerotic disease. The arteriosclerotic disease is known to be the main cause of death as in malignant tumors. In particular, the hyperlipemia is a pathological state showing a high serum cholesterol or neutral fat (TG: triglycerid or triacylglycerol) value, which in some cases occurs hereditarily, but in many cases it depends on acquired factors such as excessive eating, hyperalimentation, shortage of exercise, etc.
In animal cells, fat is accumulated as insoluble TG in large quantities therein, and depending on need of energy it is rapidly released and decomposed, and taken out as energy necessary for action. Thus, when calorie is taken over its consumption, the excessive portion is accumulated as fat. That is, TG occurring in diet is cleaved at the ester linkages in the fatty acids present at the 1 and 3 positions of TG by lipase in digestive juice in the intestine, and further decomposed to give 2-monoacylglycerol (2-MG) and free fatty acids (FFA). These are micellized along with bile acid and absorbed into the epithelial cell of small intestine. Thus absorbed 2-MG and FFA were utilized to synthesize TG again in the cell of small intestine. There are two routes in the re-synthesis of TG in the cell of small intestine, i.e., 2-MG route and α-glycerophosphate route. Usually, 80% of TG is re-synthesized in the 2-MG route, and the remaining 20% is re-synthesized in the α-glycerophosphate route. The TG generated in the 2-MG route is utilized in the formation of chylomicron (CM) in rapid turnover, whereas the TG synthesized in the α-glycerophosphate route is once accumulated because of slow turnover in the cell of small intestine and decomposed again and sometimes utilized in the formation of CM. Thus synthesized CM is secreted into the intestinal lymph to join the blood stream (non-patent document 1).
In the synthesis of TG in the 2-MG route, an enzyme such as MGAT (Acyl-CoA: monoacylglycerol acyltransferase) or DGAT (Acyl-CoA: dinoacylglycerol acyltransferase) is specifically involved therein. MGAT catalyzes the reaction in which a diacylglycerol is produced by ligation of a fatty acyl-CoA with 2-MG produced by lipase, and DGAT catalyzes the reaction in which TG is produced by ligation of a fatty acyl-CoA with the diacylglycerol produced by the catalytic reaction of MGAT.
Although it has already been suggested that such MGAT exists in the liver and white adipocyte (non-patent document 2), the gene of MGAT1, one of the MGAT family has been cloned more recently, which was isolated from mice as a molecule highly expressed in kidney, stomach, white adipocytes and brown adipocytes (non-patent document 3). Though the activity of MGAT is noticeably observed in the small intestine, MGAT1 has not been expressed in the small intestine, and the occurrence of another molecule belonging to the MGAT family has been considered.
Thereafter, Cao et al. isolated the full length cDNA of MGAT2 from a cDNA library originating in the murine small intestine by cloning of MGAT2 by homology searching based on the cDNA sequence of MGAT1 (non-patent document 4). Mouse MGAT2 is a protein of 38.6 kDa comprising 334 amino acids, which has a signal peptide of 40 amino acids at the N-terminal and at least one transmembrane domain, and can be observed to be expressed strongly in the small intestine and kidney in addition to the weak but definite expression in the stomach, liver, skeletal muscle, and spleen (non-patent document 4). In addition, Yen at al. has reported that the human and murine MGAT2 comprises 334 amino acids and their amino acid sequence has 81% homology between human (Accession No. NM—025098; SEQ ID NO: 1) and mouse (Accession No. AY157609; SEQ ID NO: 2) based on their MGAT2 cloning (non-patent document 5).
In in vitro experiments using the Sf9 cell and COS-7 cell which have been transfected with MGAT2, it has been confirmed that the MGAT activity is enhanced in the cell membrane and MGAT2 catalyzes the acylation of rac-1-monooleoylglycerol and sn-2-monooleoylglycerol (non-patent document 5). In an experiment using the COS-7 cell in which murine MGAT2 has been expressed, it has been indicated that the MGAT2 activity is stimulated with phosphatidylcholine, phosphatidylserine and phosphatidic acid and inhibited by non-ionic and zwitter ionic surfactant, suggesting the functional difference of DGAT (non-patent document 6).    Non-patent document 1: Rinsyo Iyaku (Clinical Medicines), 21, No. 2, 216 (2005);    Non-patent document 2: J. Biol. Chem., 259, 8934 (1984);    Non-patent document 3: Proc. Natl. Acad. Sci., USA, 99, 8512 (2002);    Non-patent document 4: J. Biol. Chem., 278, 13860 (2003);    Non-patent document 5: J. Biol. Chem., 278, 18532 (2003);    Non-patent document 6: J. Biol. Chem., 278, 25657 (2003).